SUMMARY OF WORK Our laboratory uses multiple approaches to investigate potential predictors of coronary heart disease in apparently healthy subjects. A. To determine whether the apoliprotein E4 allele (apo E4) is associated with an increased risk of coronary events (CE) i.e. angina pectoris, myocardial infarction or sudden death, we determined apoE genotype in 731 asymptomatic Baltimore Longitudinal Study of Aging (BLSA) volunteers followed for a mean period of 17 years. Although the 200 subjects with at least one apo E4 allele and the 531 without apo E4 had similar levels of conventional coronary risk factors, CE developed in 21% of apo E4 subjects vs. 13% in the other group. On multivariate Cox analysis, the apo E4 allele was a strong independent predictor of events (RR-1.99,p=.0005). B. We examined the relative contributions of leisure time physical activity (LTPA) and aerobic fitness (peak VO2) during treadmill exercise to development of CE in 689 clinically healthy men 18-93 years old. Over a mean follow-up of 13.4 yrs, a CE occurred in 63 (9%). In multivariate Cox model, higher peak VO2 [RR=0.53/SD] was protective against CE, both in men <65 years [RR=0.53] and those >65 years [RR=0.61/SD]. In contrast, LTPA had no independent protective effect in these community dwelling volunteers. C. We investigated whether conversion from an ischemic to a non-ischemic ST segment response to treadmill exercise is associated with a reduced risk for future CE compared with a persistent ischemic response in 421 asymptomatic BLSA volunteers. Over a mean follow-up of 8 years, CE developed in 6.3% of subjects with consistently normal ST segment responses, 15.3% of those with persistent ischemic responses and 6.4% of those who converted from an ischemic to a non-ischemic response, p<.01. Although the normal group was 20 years younger than the other two groups, the latter groups were similar in age and coronary risk factors. Thus, in asymptomatic subjects, conversion from an ischemic to a normal ST segment exercise response is associated with a normalization of coronary risk.